The invention concerns alginic acid esters in which all or only some of the carboxylic groups of the acid are esterified, and the salts of the partially esterified acid with metals or organic bases which are acceptable from a pharmacological point of view.
The compounds possess interesting and valuable bioplastic and pharmaceutical qualities and may be used in numerous fields, from cosmetics to surgery and medicine. The invention also includes pharmaceutical preparations containing as an active ingredient one or more alginic acid esters or one of their salts as described above, as well as medicaments containing:
1) a pharmacologically active substance or an association of pharmacologically active substances and, PA1 2) a carrying vehicle comprising a totally or partially esterified alginic acid.
The invention also includes various uses of alginic esters or the above mentioned medicaments, such as in the fields of medicine, surgery or cosmetics and a new procedure for the preparation of alginic acid esters.
Alginic acid is a natural acidic polysaccharide extracted above all from so-called brown algae (Phaecophyceae) with a high molecular weight varying between about 30,000 and 200,000, and containing chains formed by D-mannuronic acid and L-guluronic acid. The degree of polymerization varies according to the type of alga used for extraction, the season in which the algae were gathered and the place of origin of the algae, as well as the age of the plant itself. The main species of brown algae used to obtain alginic acid are, for example, Macrocystis pyrifera, Laminaria cloustoni, Laminaria hyperborea, Laminaria flexicaulis, Laminaria digitata, Ascophyllum nodosum, Fucus serratus.
Alginic acid is found in these algae as an extensive constituent of the cell walls in the form of a mixture of some of its alkaline salts, of these especially sodium salt. This mixture is also known as "algin". These salts are normally extracted in aqueous conditions with a sodium carbonate solution and it is possible to obtain alginic acid directly from this extract by precipitation with an acid, for example a mineral acid such as hydrochloric acid. An indirect preparation procedure involves first making an insoluble calcium salt by adding a soluble calcium salt, such as chloride, and after washing this salt, alginic acid is obtained again by treatment with an acid.
Alginic acid or alkaline alginates may, however, also be obtained microbiologically, for instance by fermentation with Pseudomonas aeruginosa or mutants of Pseudomonas putida, Pseudomonas fluorescens or Pseudomonas mendocina.
The metal salts of alginic acid, especially the alkaline and alkaline earth metal salts, have interesting chemical and physical properties and are therefore widely used in industry, Thus, for example, the solutions of alkaline or alkaline earth alginates are extremely suitable, due to their viscosity, and their adjustability by temperature and pH, for the preparation of gels which may be widely used in the food industry, for the preparation of ice creams, milk puddings and many other types of cakes and puddings. Another property which is widely exploited in the field of alimentation is the ability of alginates to retain water, and for this reason they are used for example for the conservation of many types of frozen foods. A third property of alginates is their power to emulsify and to stabilise emulsions; for this reason too these salts are important in the food industry, where they are used for the preparation of condiments and for the stabilisation of many types of drink, such as beer or fruit juices, sauces and syrups.
The ability of alginate solutions to form films and fibres has been exploited in the paper industry, in making adhesive labels, in textile printing and dyeing, and in the preparation of sanitary, medical and surgical articles. Alginates are used as emulsifiers for the preparation of polishes, antifoam agents, lactics and as stabilisers in the ceramic and detergent industries (for a more detailed list see for example "The Polysaccharides", Vol. 2, by Paul A. Sandford and John Baird, Copyright 1983 by Academic Press., Inc.).
Alginic acid and its salts have also been used however in the pharmaceutical, medical, surgical and cosmetic fields, for example for the preparation of medicaments for topical use and sanitary and surgical articles. For example the German Offenlegungsschrift 3 017 221 (20.11.1980), discloses an "artificial skin" for use in serious lesions of the skin, for example following burns, in which an ointment containing a soluble alginate of an alkaline metal is applied topically to the skin and treated in situ with a soluble calcium salt. This causes the formation of insoluble calcium alginate, transforming the layer of ointment into an easily tolerated biologically protective film, with structural and mechanical physical characteristics similar to those of natural skin.
Calcium alginate has been used for the manufacture of fibres for use in the pharmaceutical industry French patent application No. 2.418 821 (28.9.1979), Rumanian Patent No.70 069 (30.6.1980) contains the description of a healing and antiseptic medicament for skin wounds, made from calcium alginate fibres. Calcium alginate is also used as a hemostatic agent in the form of bandages or gauses containing fibres of the salt. Other medicaments based on calcium alginate are used for the treatment of sinoids, fistulas, and in the treatment of nosebleeds. In Galenism, sodium and calcium alginates are also used as disintegrators for pills, and sodium alginate is also used for its binding properties.
Also used in industry in many of the abovementioned fields are two alginic acid esters or salts of such esters, more precisely ethylene glycol and propylene glycol esters. The latter is used for example as an emulsifier and stabiliser for foodstuffs. (See for example "Martindale"- The Extra Pharmacopoeia, p. 931 and "The Polysaccharides", Vol. 2, Copyright by Academic Press, Inc. 1983, pp. 448-449). The above mentioned esters have been obtained by reaction of alginic acid, or its salt or partial salt, with ethylene or propylene oxide respectively. This preparation method is also the basis of patents for the preparation of the above mentioned alginic acid esters and esters of bivalent alcohols by reaction of an aliphatic hydrocarbon epoxide, possibly substituted or interrupted by hetero atoms in the carbon atom chain (see for example U.S. Pat. Nos. 2,463,824-2,426,125-2,463,824, German Offenlegungsschriften 2,161,415-2,046,966-2,641,303-2,529,086, Japanese Patent Nos. 2027 ('59) and 72 47 858, and French Patent No. 2247204.
The alginic acid esters obtainable by the action of the above mentioned epoxides on the free acid or its salts are partial esters (see A. B. Steiner, Industrial and Engineering Chemistry, Vol.43, pp. 2073-2077, 1951), with a maximum degree of esterification of about 80% of all the existing carboxylic groups in the case of glycol esters with a low molecular weight, and a very low degree in the case of glycol esters with long chains. It has not been possible until now to prepare total esters by this method.
Monovalent alcohol esters, both aliphatic and araliphatic have also been mentioned in literature, above all a methyl ester of alginic acid obtained by reaction of alginic acid in an ethereal solution of diazomethane. (Zeitschrift fuer physiologische Chemie, Vol. 293, p. 121, 1953, A. B. Steiner, Industrial and Engineering Chemistry, Vol. 43, p. 2073, 1951, U.K. Patent No. 768,309. It seems however that the products obtained by reaction with diazomethane are not really alginic acid esters but rather methyl esters of an alginic acid partially etherified to the hydroxy alcohol groups, as described for example in Example 4 of the above mentioned U.K. patent. One methyl ester has also been obtained by reaction of dimethyl sulphate on a soluble salt of alginic acid in an organic solvent with low solubility in water, but in the presence of water (U.S. Pat. No. 2,860,130). The product obtained, referred to as methyl alginic acid or methyl alginate, is not to be considered as a pure ester, since it is known that sugar hydroxyls are easily etherified with this methylating agent. This case, therefore, also is truly a mixed ester-ether.
Also mentioned in literature are alginic acid esters of monovalent alcohols, with no indication however of their preparation method and no description of their chemical and physical properties. As no preparation method is known, apart from the above mentioned reaction with diazomethane and dimethyl sulphate, it is probable that the use of homologues of these esterifying agents to obtain esters of the homologous series of the methyl ester are not practical at all, or at the most they result in mixed products, as in the case of methyl products. (See for example U.S. Pat. No. 4,216,104 in which a propyl alginate is mentioned with no indication of its origin or preparation method, and the Japanese Kokai No. 55-132781, page 5, in which ethyl, butyl, lauryl, oleyl, phenyl and benzyl esters are mentioned, with no indication as to how they are obtained).
On the basis of these facts therefore, it is presumed that of all alginic acid esters only those esters of bivalent alcohols are known, and more precisely only alginic acid partially esterified with glycols, since by the known method used in industry, it is difficult to achieve complete esterification and in the commercial product no less than 10% of the carboxyls remain unesterified in their free carboxy form, possibly salified.